Painless brown macules on the lips and fingers

Peutz-Jeghers syndrome is a genodermatosis characterized by mucocutaneous pig­mented lesions, GI polyposis, and an increased risk of cancer. Peutz-Jeghers syndrome is inherited in an autosomal-dominant fashion; however up to 25% of cases are sporadic.1 The incidence is estimated to be...

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Peutz-Jeghers syndrome is a genodermatosis characterized by mucocutaneous pig­mented lesions, GI polyposis, and an increased risk of cancer. Peutz-Jeghers syndrome is inherited in an autosomal-dominant fashion; however up to 25% of cases are sporadic.¹

The incidence is estimated to be approximately 1 in 8,300 to 1 in 200,000 live births.¹ There are no reported variations based on ethnicity. Given the autosomal-dominant inheritance, males and females are equally affected.

The majority of cases of Peutz-Jeghers syndrome are caused by mutations in the STK11/LKB1 gene on chromosome 19p13.13. This gene encodes a serine/threonine protein kinase that is thought to act as a tumor suppressor. This mutation is found in 52% to 70% of cases.¹

The exact mechanisms by which the loss of STK11/LKB1 activity triggers the cutaneous findings and increased risk of cancer is unknown.² This serine/threonine kinase may be involved in transduction of intracellular growth signals and in Wnt signaling.¹ It has also been hypothesized that STK11/LKB1 regulates p53-mediated apoptotic pathways and regulates cell proliferation via G1 cell-cycle arrest and WAF1 signaling.^3,4 Mutations in STK11/LKB1 gene may also alter cell polarity, which is thought to play a role in tumor formation.³

Brown macules on the lips and oral mucosa are the most characteristic cutaneous findings of Peutz-Jeghers syndrome. The lower lip is most commonly affected. These macules tend to develop in infancy or early childhood. In terms of the oral mucosa, the buccal mucosa, tongue, or gingiva may be affected. Similar lesions may also be found on the genital mucosa. Up to 95% of patients may have perioral lesions. Two-thirds of patients may have lesions on the hands and feet, especially the fingers, toes, dorsal hands, and dorsal feet.⁵

GI polyposis most commonly affects the small intestine and is involved in 64% of patients. These polyps also commonly affect the stomach and colon in approximately 49% of patients. The rectum is only involved in one-third of patients.⁵ The median time of first presentation with GI polyposis is age 11 years to age 13 years.⁶ Presenting signs include abdominal pain, vomiting, GI bleeding, and intussusception.⁵

It has been estimated that Peutz-Jeghers syndrome confers a 15-fold greater lifetime risk of GI and non-GI cancers compared with the general population.^5,7 The increased lifetime risk of GI cancer is as follows: colon (39%), pancreas (36%), stomach (29%), small intestine (13%), and esophagus (0.5%).⁸

Persons with Peutz-Jeghers syndrome have an increased lifetime risk of breast cancer (54%), lung cancer (15%), ovarian cancer (21%), and uterine cancer (9%).⁸ Breast cancer can be bilateral.⁸ Cervical and thyroid cancers have also been reported in the literature.

Sertoli-Leydig cell stromal tumors can occur in males, and sex-cord tumors with annular tubules (SCAT) can occur in female patients with Peutz-Jeghers syndrome.⁵ This latter finding is considered to be a classic feature of Peutz-Jeghers syndrome, as 36% of women who are diagnosed with SCAT are found to have Peutz-Jeghers syndrome.⁹ Even in patients without the STK11/LKB1 mutation, there is a 40% risk of cholangiocarcinoma.⁵

The diagnosis of Peutz-Jeghers syndrome is made clinically by the presence of two or more of the following features:

1. Two or more Peutz-Jeghers polyps of the small intestine characterized by a distinctive pattern of arborization of the muscularis mucosa
2. Characteristic pigmentation of the mouth, lips, nose, eyes, genitalia, or fingers
3. Family history of Peutz-Jeghers syndrome.⁹

The differential diagnosis of Peutz-Jeghers syndrome includes inherited patterned lentiginosis, Laugier-Hunziker syndrome, and Cronkhite-Canada syndrome. Inherited pattern lentiginosis was first described in 10 patients of African-American heritage.¹⁰ More recently, however, familial generalized lentiginosis was described in a four-generation Chinese family.¹¹ Unlike Peutz-Jeghers syndrome, there are no internal abnormalities in inherited pattern lentiginosis.

Similar to Peutz-Jeghers syndrome, Laugier-Hunziker syndrome is characterized by macular hyperpigmentation of the oral mucosa, including the lips. However, the hyperpigmented macules on the oral mucosa in Laugier-Hunziker syndrome develop in the early- to mid-adult years, which is a much later onset than that seen in Peutz-Jeghers syndrome.¹²

A distinctive feature of Laugier-Hunziker syndrome is longitudinal melanonychia that can occur on the fingernails, toenails, or both.¹² In contrast to Peutz-Jeghers syndrome, patients with Laugier-Hunziker syndrome lack the pigmented macules on the hands and feet and also do not develop GI polyposis.¹²

Cronkhite-Canada syndrome is a noninherited condition also characterized by hyperpigmentation and GI polyposis. Although both Cronkhite-Canada syndrome and Peutz-Jeghers syndrome can present with brown macules with a predilection for the lips, face, oral mucosa, hands, and feet, Cronkhite-Canda syndrome has distinctive cutaneous features of diffuse hyperpigmentation, discoloration and dystrophy of the fingernails and toenails, and alopecia.

Other possible skin findings include xanthelasma and papillary atrophy of the tongue. Cronkhite-Canada syndrome is also characterized by edema, muscle wasting, ocular manifestations (streaks of tan pigment in the retina, cataracts), and acute psychotic symptoms.^13,14

The treatment of mucocutaneous pigmentation associated with Peutz-Jeghers syndrome is only necessary if the lesions are cosmetically distressing to the patient. Surgical excision, cryosurgery, electrodesiccation, dermabrasion, and ablative laser (CO2 or argon) therapy are not recommended due to the risks of incomplete removal, scarring, and dyspigmentation.¹⁵

Successful treatment of mucocutaneous lentigines has been reported with potassium titanyl phosphate, intense pulsed light, ruby, Q-switched ruby, and Q-switched alexandrite lasers.^15-18 GI polyposis may be treated with laparotomy, polypectomy, and/or bowel resection. Colectomy may be considered for recurrent or unresectable polyps.¹⁹

Because of the high risk of cancer, the following screening guidelines have been recommended for all patients with Peutz-Jeghers syndrome:

1. Upper endoscopy, colonoscopy, and abdominal CT with oral contrast every two to three years beginning at age 10 years
2. Magnetic resonance cholangiopancreatography and/or endoscopic ultrasound every one to two years by age 30 years.

Female patients are advised to undergo:

1. Annual mammogram and breast MRI with clinical breast exam every six months beginning by age 25 years
2. Annual pelvic examination, pelvic ultrasound, and Pap smear by age 20 years.

Male patients are advised to undergo annular testicular exam and observation for feminizing changes by age 10 years.⁹

Unfortunately, the patient described in this case was lost to follow-up.

Audrey Chan, MD, is a third-year dermatology resident at Baylor College of Medicine in Houston. William Longhurst is a fourth-year student at the University of North Dakota School of Medicine & Health Sciences in Grand Forks.